One line of transgenic mice has been extensively studied. This line has the human immunodeficiency viral protease (HIV-1) linked to the alpha-A-crystallin promoter. The homozygous animals all get cataracts on day 23 to day 24 after birth. Previously, we have examined the protein changes that occur in the lenses of these animals over time. We have now concentrated on the main intrinsic membrane protein of the lens. This protein is degraded during the formation of the cataract, and the degradation occurs in the same time period that there is an influx of water into the lens. The cleavage of this protein is at the carboxyl terminal. According to other data on this protein, the loss of the carboxyl terminal would cause this channel protein to be stuck in the open position, allowing water to flow into the cell. The degradation of this protein would appear to cause the change in hydration of the lens and the opacification. Curiously, the HIV-1 protease does not cleave this molecule in vitro. Unlike other proteins in the lens, the main intrinsic membrane protein is not altered during a 24-hour incubation with the HIV-1 protease. The pattern of cleavage is similar to that obtained when the protein is incubated with a cysteine protease such as calpain. Organ culture studies have shown cataract formation will occur ex vivo if the precataractous lens is placed into organ culture. The cataract can be delayed by inhibitors of cysteine proteases. These results would suggest that the HIV-1 protease activates a cysteine protease that is latent in the lens and that the activation of this protease is the event that eventually leads to opacification.